`1 Docket Number—'- 4—32219A FILING sv "EXPRESS MAIL“ UNDER 37 OFF-21.10
`'
`January 14, 2993
`swaszzssss
`Date of Deposit
`_. Esme—5s Mail Label Number
`
`
`
`
`
`
`Address to Assistant Commissioner for Patents
`Box Patent Application
`Washington. DC 20231
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`Transmitted herewith for filing under 37 CFR §1.53(b) is the utility patent application of
`
`Applicant (or identifier): KSANDER ET AL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`COMPOSITION
`
`EDDIE]
`
`“3.057491
`
`10.
`11.
`12.
`
`NEBWDF‘FI
`
`
`Specification (Including Claims and Abstract) - 26 pages
`Drawings -
`sheets
`Executed Declaration and Power of Attorney (original or copy)
`Microfiche Computer Program (appendix)
`Nucleotide andfor Amino Acid Sequence Submission
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`English Translation of
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`
`Filing fee calculation:
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`I
`
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`
`

`

`-----
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`
`
`N Please charge Deposit Account No. 19—0134 in the name of Novartis Corporation in the
`amount of $740. An additional copy of this paper is enclosed. The Commissioner is
`hereby authorized to charge any additional fees under 37 CFR §1_16 and §1.17 which may
`be required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19—0134 in the name of Novartis Corporation.
`
`Please address all correspondence to the address associated with Customer No. 001095, which
`is currently:
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`
`Please direct all telephone calls to the undersigned at the number given below, and all telefaxes
`to (862) 778-8064.
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`Date: January 14, 2003
`
`Respectfully submitted,
`
`
`
`raro
`regory D. F
`Attorney for pplicants
`Reg. No. 36,134
`Tel. No. (862) 778-7831
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 002
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 002
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`

`
`1 Docket Number—'- 4—32219A FILING sv "EXPRESS MAIL“ UNDER 37 OFF-21.10
`'
`January 14, 2993
`swaszzssss
`Date of Deposit
`_. Esme—5s Mail Label Number
`
`
`
`
`
`
`Address to Assistant Commissioner for Patents
`Box Patent Application
`Washington. DC 20231
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`Transmitted herewith for filing under 37 CFR §1.53(b) is the utility patent application of
`
`Applicant (or identifier): KSANDER ET AL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`COMPOSITION
`
`EDDIE]
`
`“3.057493
`
`10.
`11.
`12.
`
`NEBWDF‘FI
`
`
`Specification (Including Claims and Abstract) - 26 pages
`Drawings -
`sheets
`Executed Declaration and Power of Attorney (original or copy)
`Microfiche Computer Program (appendix)
`Nucleotide andfor Amino Acid Sequence Submission
`1:] Computer Readable Copy
`E1 Paper Copy
`1:] Statement Verifying Identity of Above Copies
`Preliminary Amendment
`Assignment Papers (Cover Sheet & Document(s))
`English Translation of
`Information Disclosure Statement
`
`Certified Copy of Priority Document(s)
`Return Receipt Postcard
`Other: unsigned Declaration and Application Data Sheet
`
`Filing fee calculation:
`
`Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`1:]
`Before calculating the filing fee, please cancel claims
`:1
`
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`__74d
`Basic Filing Fee
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`1 ForeijgrlLanguage Surchar e 3 900)
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`For
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`Filed
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`_
`Extra
`Rate
`
`Extra
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`x
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`= ]$
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`Claims
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`Independent
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 003
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 003
`
`I
`
`I I
`
`'.l l.
`]
`1111]]
`I] l
`1|]
`II
`"'"IIII
`III'11”
`II
`
`Ii
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`Elli]
`
`

`

`-----
`
`
`
`N Please charge Deposit Account No. 19—0134 in the name of Novartis Corporation in the
`amount of $740. An additional copy of this paper is enclosed. The Commissioner is
`hereby authorized to charge any additional fees under 37 CFR §1_16 and §1.17 which may
`be required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19—0134 in the name of Novartis Corporation.
`
`Please address all correspondence to the address associated with Customer No. 001095, which
`is currently:
`Thomas Hoxie
`
`Novartis Pharmaceuticals Corporation
`Patent and Trademark Dept.
`One Health Plaza
`
`East Hanover, NJ 07936-1080
`
`Please direct all telephone calls to the undersigned at the number given below, and all telefaxes
`to (862) 778-8064.
`
`Date: January 14, 2003
`
`Respectfully submitted,
`
`
`
`raro
`regory D. F
`Attorney for pplicants
`Reg. No. 36,134
`Tel. No. (862) 778-7831
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 004
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 004
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`

`

`-.|i
`Ii
`ii
`..:u
`lNVENTOR INFORMATION
`
`
`Inventor One Given Name:: Gary M
`Family Name:: Ksander
`Postal Address Line One:: 342 Woolf Road
`City:: Milford
`State or Province:: New Jersey
`
`Country:: United States of America
`Postal or Zip Code:: 08848
`City or Residence:: Milford
`State or Province of Residence:: New Jersey
`
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`Inventor Two Given Name:: Randy L
`
`Hamiiy Name:: Webb
`Postal Address Line One::
`
`;7 Honevman Drive
`
`
`
`Cityzz Flemington
`State or Province:: New Jersey
`
`Country:: United States of America
`Postal or Zip Code:: 08822
`,
`City of Residence:: Eieminqton
`State or Province of Residence:: New Jersey
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`
`CORRESPONDENCE INFORMATION
`
`Correspondence Customer Number:: 001095
`
`APPLICATION INFORMATION
`
`
`Title Line Onezz METHODS OF TREATMENT AND iJl1ARMACIi-ZUTIZCAI.
`”itle Line Two::
`COMPOSITION
`
`
`
`?orma1 Drawings?:: No
`Application Type:: Utility
`Docket Number:: 4—32219A
`
`
`
`Secrecy Order in Parent Appl.?:: No
`
`
`CONTINUITY INFORMATION
`
`NON PROV. OF PROVESTONAL
`This application is a::
`60/386,792
`> Application Onez:
`
`Filing Date::
`06~07—?002
`
`NON PROV. OF PROVISIONAL
`This application is a::
`60/349,660
`> Application Twoz:
`Filing Date::
`01—17—2002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 005
`IBIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 005
`
`

`

`SOUFCOZZ
`
`PrintEFS VersLon 1.0.1
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 006
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`
`

`

`
`
`Case 4-32219A
`
`METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION
`
`Background of the Invention
`
`The renin angiotensin system is a complex hormonal system comprised of a large
`
`molecular weight precursor, angiotensinogen, two processing enzymes, renin and
`
`angiotensin converting enzyme (ACE), and the vasoactive mediator angiotensin II (Ang II).
`
`See J. Cardiovasc. Pharmacol._ Vol, 15, Suppl. B, pp. 81—85 (1990}. The enzyme renin
`
`catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin I, which has
`
`minimal biological activity on its own and is converted into the active octapeptide Ang II by
`ACE. Ang II has multiple biological actions on the cardiovascular system, including
`
`vasoconstriction, activation of the sympathetic nervous system, stimulation of aldosterone
`
`production, anti—natriuresis, stimulation of vascular growth and stimulation of cardiac
`growth. Ang II functions as a pressor hormone and is involved the pathophysiology of
`
`several forms of hypertension.
`
`The vasoconstrictive effects of angiotensin Ii are produced by its action on the non—
`
`striated smooth muscle cells, the stimulation of the formation of the adrenergenic hormones
`epinephrine and norepinephrine, as well as the increase of the activity of the sympathetic
`nervous system as a result of the formation of norepinephrine. Ang II also has an influence
`
`on electrolyte balance, produces, e.g., anti—natriuretic and anti—diuretic effects in the kidney
`and thereby promotes the release of, on the one hand, the vasopressin peptide from the
`pituitary gland and, on the other hand, of aldosterone from the adrenal glomerulosa. All
`these influences play an important part in the regulation of blood pressure, in increasing
`
`both circulating volume and peripheral resistance. Ang II is also involved in cell growth and
`
`migration and in extracellular matrix formation.
`
`Ang II interacts with specific receptors on the surface of the target cell.
`
`It has been
`
`possible to identify receptor subtypes that are termed, e.g., AT 1- and AT 2-receptors.
`recent times great efforts have been made to identify substances that bind to the AT 1—
`
`in
`
`receptor. Such active ingredients are often termed Ang Ii antagonists. Because of the
`inhibition of the AT 1—receptor such antagonists can be used, e.g_, as anti-hypertensives or
`
`for the treatment of congestive heart failure. among other indications. Ang ll antagonists
`
`are therefore understood to be those active ingredients which bind to the AT t—receptor
`
`subtype.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 007
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 007
`
`

`

`
`
`Inhibitors of the renin angiotensin system are well—known drugs that lower blood
`
`pressure and exert beneficial actions in hypertension and in congestive heart failure as
`
`described. See, e.g, N. Eng. J. Med, Vol. 316, N0. 23. pp. 1429w1435(1987). A large
`
`number of peptide and non—peptide inhibitors of the renin angiotensin system are known, the
`
`most widely studied being the ACE inhibitors, which includes the drugs captOpril, enalapril,
`
`lisinopril, benazepril and spirapril. Although a major mode of action of ACE inhibitors
`
`involves prevention of formation of the vasoconstrictor peptide Ang II, it has been reported
`
`in Hypertension, Vol. 16, No. 4, pp. 353-370 (1990), that ACE cleaves a variety of peptide
`
`substrates, including the vasoactive peptides bradykinin and substance P. Prevention of the
`
`degradation of bradykinin by ACE inhibitors has been demonstrated, and the activity of the
`
`ACE inhibitors in some conditions has been reported in Circ. Res, Vol. 66, No. 1, pp. 242-
`
`248 (1990), to be mediated by elevation of bradykinin leveis rather than inhibition of Ang II
`
`formation. Consequently, it cannot be presumed that the effect of an ACE inhibitor is due
`
`solely to prevention of angiotensin formation and subsequent inhibition of the renin
`
`angiotensin system.
`
`Neutral endopeptidase {EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc—
`
`containing metalloprotease that cleaves a variety of peptide substrates on the amino
`
`terminal side of aromatic amino acids. See Biochem. J., Vol. 241, pp. 237—247 (1987),
`
`Substrates for this enzyme include, but are not limited to, atrial natriuretic factors (ANFs),
`
`also known as ANPs, brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin,
`
`neurokinin A and substance P.
`
`ANPs are a family of vasodilator, diuretic and anti-hypertensive peptides which have
`
`been the subject of many recent reports in the literature. See, e.g., Annu. Rev. Pharm.
`
`Tox., Vol. 29, pp. 23—54 (1989). One form, ANF 99-126, is a circulating peptide hormone
`
`which is released from the heart during conditions of cardiac distension. The function of
`
`ANF is to maintain salt and water homeostasis, as well as to regulate blood pressure. ANF
`
`is rapidly inactivated in the circulation by at least two processes: a receptor-mediated
`
`clearance reported in Am. J. Physiol, Vol. 256, pp. R469-R475 (1989), and an enzymatic
`
`inactivation via NEP reported in Biochem. J., Vol. 243, pp. 183—187 (1987).
`
`It has been
`
`previously demonstrated that inhibitors of NEP potentiate the hypotensive, diuretic,
`
`natriuretic and plasma ANF responses to pharmacological injection of ANF in experimental
`
`animals. The potentiation of ANF by two specific NEP inhibitors is reported by Sybortz et
`
`al., J. Pharmacol, Exp. Ther., Vol. 250, No. 2, pp. 624-631 (1989), and in Hypertension, Vol.
`
`15, No. 2, pp. 152—161 (1990), while the potentiation of ANF by NEP in general was
`
`_2~
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 008
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 008
`
`

`

`
`
`I disclosed in U.S. Patent No. 4,749,688.
`
`In US. Patent No. 4,740, 499, Olins disclosed the
`
`use of thiorphan and kelatorphan to potentiate atrial peptides. Moreover, NEP inhibitors
`
`lower blood pressure and exert ANF—like effects, such as diuresis and increased cyclic
`
`guanosine 3'.5'-monophosphate (cGMP) excretion in some forms of experimental
`
`hypertension. The anti—hypertensive action of NEP inhibitors is mediated through ANF
`
`because antibodies to ANF will neutralize the reduction in blood pressure.
`
`Darrow et al. in European Patent Application No. 498361 disclose treating
`
`hypertension or congestive heart failure with a combination of certain Ang II antagonists or
`
`certain renin inhibitors with certain NEP inhibitors.
`
`Powell et al. in European Patent Application No. 726072 disclose treating
`
`hypertension or congestive heart failure with a combination of the Ang II antagonist 2—butyl—
`
`8,7,8,9—tetrahydro-3-[[2'—(1f-l-tetrazol-5-yl)[‘l ,1'-biphenyl]—4—yl]methyI]—1 ,3—
`
`diazaspiro[4.4]nonan-4-one with a NEP inhibitor or a dual acting vasopeptidase inhibitor
`
`(single molecular entity with both ACE and NEP inhibitory activities). Prolonged and
`uncontrolled hypertensive vascular disease ultimately leads to a variety of pathological
`
`changes in target organs, such as the heart and kidney. Sustained hypertension can lead
`
`as well to an increased occurrence of stroke. Therefore, there is a strong need to evaluate
`
`the efficacy of anti—hypertensivetherapy, an examination of additional cardiovascular _
`
`endpoints, beyond those of blood pressure lowering, to get further insight into the benefits of
`combined treatment.
`
`The nature of hypertensive vascular diseases is multifactorial. Under certain
`
`circumstances, drugs with different mechanisms of action have been combined. However,
`
`just considering any combination of drugs having different mode of action does not
`necessarily iead to combinations with advantageous effects. Accordingly, there is a need
`
`for more efficacious combination therapy which has tess deleterious side effects.
`
`Other objects, features, advantages and aspects of the present invention will become
`
`apparent to those of skill from the following description.
`
`It should be understood, however,
`
`that the following description and the specific examples, while indicating preferred
`
`embodiments of the invention, are given by way of illustration only. Various changes and
`
`modifications within the spirit and scope of the disclosed invention will become readily
`
`apparent to those skilled in the art from reading the following description and from reading the
`
`other parts of the present disclosure.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 009
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 009
`
`

`

`Detailed Descrigtion of the Preferred Embodiments
`
`
`
`in one aspect, the present invention relates to pharmaceutical combinations
`comprising Ualsartan or pharmaceutically acceptable salts thereof and a NEP inhibitor or a
`pharmaceutically effective salts thereof, optionally in the presence of a pharrriaceuticailyr
`acceptable carrier and pharmaceutical compositions comprising them.
`
`In another embodiment, the present invention relates to methods of treating cardiac
`
`and renal related conditions by administration of the pharmaceutical composition comprising
`
`valsartan plus a NEP inhibitor.
`
`Valsartan is the AT i—receptor antagonist (SJ-N-(‘l—carboxy—2—methyI—prop—1 —yI)—N—
`
`pentanoyl-N—[Z;(1H—tetrazoI—S—yl)biphenyI—4-yI-methyi]amine of formula (I)
`
`I
`CH
`
`CH?
`CH2
`
`2x
`
`CH3\
`HC
`
`0
`
`/CH3
`
`(1)
`
`HN \ N
`\
`f
`N“—N
`
`and is disclosed in EP 0443983 A and US. Patent No, 5,399,578, the disclosures of which
`
`are incorporated herein in their entirety as if set forth herein.
`
`A NEP inhibitor useful in said combination is a compound of the formula (II)
`
`it
`I
`i3
`if
`T2
`HS—CHz—CH—C" -NH—CH—(CH2);”C—R1
`
`(“l
`
`and pharmaceuticaily acceptable salts thereof,
`wherein
`
`R2 is alkyl of 1 to 7 carbons, trifluoromethyl, phenyl, substituted phenyl, -(Cl-lp)1 m 4-
`
`phenyl, or —(CH2)1 to 4~substituted phenyl;
`
`R3 is hydrogen, alkyl of “l to 7 carbons, phenyl, substituted phenyl, —(CH;_~)1m4-phenyl, or
`
`—(l'.3H2)1 to [substituted phenyl;
`
`R1 is hydroxy, alkoxy OH to 7 carbons, or NH;
`
`-4-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 010
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 010
`
`

`

`
`
`n is an integer from 1 to 15; and
`
`the term substituted phenyl refers to a substituent selected from lower alkyl of 1 to 4
`
`carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, hydroxy, Cl, Br or
`F.
`
`Preferred selective NEP inhibitors of formula (II) include compounds,
`wherein
`
`R2 is benzyl;
`
`R3 is hydrogen;
`
`n is an integer from 1 to 9; and
`
`R1 is hydroxy.
`
`Even more preferred selective NEP inhibitors of formula (II) are reported in the
`
`literature as SQ 28,603 which is the compound of formula (II),
`wherein
`
`R;- is benzyl;
`
`R3 is hydrogen;
`
`n is one; and
`
`R1 is hydroxy.
`
`The preparation of the selective NEP inhibitors of formula (II), wherein R2 is other
`
`than trifluoromethyl are disclosed by Delaney et al.
`
`in US. Patent No. 4,722,810. The
`
`preparation of the selective NEP inhibitors of formula (II), wherein R2 is trifluoromethyl are
`
`disclosed by Delaney et al. in US. Patent No. 5,223,516.
`
`NEP inhibitors within the scope of the present invention include compounds
`
`disclosed in U.S. Patent No. 4,610,816, herein incorporated by reference, including in
`
`particular N—[N—[1(S)-carboxyl—3—pheny]proplyl]—(S)—phenylalanyl]—(S)—isoserine and N—[N—
`
`[((1S)-carboxy—2—phenyl)ethyl]—(S)~phenylalanyl]-[3-alanine; compounds disclosed in US.
`
`Patent No. 4,929,641, in particular, N—[2(S)~mercaptomethyl—3—(2—methylphenyl)—
`
`propionyl]methionine; 80 28603 (N-[2—(mercaptomethyl)-1-oxo-3—phenylpropyl]—[i—alanine),
`
`disclosed in South African Patent Application No. 84f0670; UK 695?8 (cis-4-[[[1-[2-carboxy—
`
`3—(2—methoxyethoxy)propyl]—cyclopentyl]carbonyl]amino]—cyclohexane'carboxylic acid) and its
`
`active enantiomer(s); thiorphan and its enantiomers; retro-thiorphan; phoSphoramidon; and
`
`-5-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 011
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 011
`
`

`

`
`
`SQ 29072 (7—[[2-(mercaptomethy|)—1—oxo—3-phenylpropyl]amino]—heptanoic acid). Also
`
`suitable for use are any pro-drug forms of the above—listed NEP inhibitors, e.g., compounds
`
`in which one or more carboxylic acid groups are esterified.
`
`NEP inhibitors within the scope of the present invention also include the compounds
`
`disclosed in US, Patent No. 5,217,996, particularly, N—(3—carboxy~1-oxopropyl)—(4S)—p-
`
`phenylphenylmethyl)~4-amino-2R—methylbutanoic acid ethyl ester; the compounds disclosed
`
`in EP 00342850, particularly, (S)—cis-4-[1-[2-(5-indanyloxycarbonyl)«3-(2-
`
`methoxyethoxy)propyl]-1-cyclopentanecarboxamido]-1-cyclohexanecarboxylic acid; the
`
`compounds disclosed in GB 02218983, particularly, 3~(‘l—[6—endo—
`
`hydroxymethylbicyclo[2,2,1]heptane~2—exo-carbamoyl]cyclopentyl)—2—(2—
`
`methoxyethyl)propanoic acid; the compounds disclosed in WC) 92104706, particularly,
`
`N—(1—(3—(N—t—butoxycarbonyI—(S)—prolylamino)-2(S}-t-butoxy- _
`
`carbonylpropyI)cyclopentanecarbonyl)-O-benzyl—(S)—serine methyl ester; the compounds
`
`disclosed in EFJ 00343911; the compounds disclosed in JP 06234754; the compounds
`
`disclosed in EP 00361365, particularly, 4—[[2—(mercaptomethyl)—1—oxo—3—
`
`phenylpropyl]aminojbenzoic acid; the compounds disclosed in WO 90109374, particularly,
`3-[1-(cis—4—carboxycarbonyl—cfs—3—butylcyclohexylsr-1-oarboamoyl)cyclopentyl]—2S—(2—
`
`methoxyethoxymethyl)propanoic acid; the compounds disclosed in JP 07157459,
`
`particularly, N-((2S)—2—(4~biphenylmethyl}-4-carboxy-5-phenoxyvaleryl}glycine; the
`
`compounds disclosed in WC 94.115908, particularly, N-(1-(N-hydroxycarbamoylmethy|)—1—
`
`cyclopentanecarbonyl)-L-phenylalanine; the compounds disclosed in US. Patent No.
`
`5,273,990, particularly, (S)-(2-biphenyl-4-yl)—1-(TH—tetrazol-S-yl)ethylamino)
`
`methylphosphonic acid; the compounds disclosed in US. Patent No. 5,294,632, particularly,
`
`(S)—5—(N—(2-(phosphonomethylamino)—3—(4—bipheny|)propionyl)—2—aminoethyl)tetrazolej. the
`
`compounds disclosed in US. Patent No. 5,250,522, particularly, B-Alanine, 3~[1,1'—biphenyl}—
`
`4—yl—N—{diphenoxyphosphinyl)methyl]—L-alanyl; the compounds disclosed in EP 00636621,
`
`particularly, N—{2-carboxy-4-thienyl)—3—mercapto—2—benzylpropanamide; the compounds
`
`disclosed in WO 93109101, particularly, 2-(2-mercaptomethyl—3—phenylpropionamido)thiazol-
`
`4—ylcarboxylic acid; the compounds disclosed in EP 00590442, particularly, ((L)—I_(1—((2,2—
`
`dimethyl—1,3—dioxolan-4-yl)-methoxy)carbonyl)-2-pheny]ethyl)-L-phenylalanyl)-B-alanine, N—
`
`[N—[(L)-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalany|]—
`
`(R)—alanine, N—[N—[(L}-1-carboxy-2-phenylethyl]-L-phenylalanyl]-(R)-alanine, N—[2—
`
`acetylthiomethyl—3—(2—methyt—phenyl)propionyl]~methionine ethyl ester, N—[2—mercaptomethyl—
`
`3—(2—methylphenyl}propioyl]—methionine, N-[2(S)-mercaptomethyl-3-(2-
`
`methylphenyl)propanoyl]-(S)—isoserine, N—(S)—[3—mercapto—2—(2—methylphenyl)propionyl]~(S)-
`
`-5-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 012
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 012
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`

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`- 2-methoxy-(R)-a|anine, N—[1—[[‘l(S)-benzy|oxycarbonyl—3—
`
`phenylpropyl]amino]cyclopentylcarbonyl]—(S)—isoserine, N-[1 -[[‘l(S)—carbonyl—3—
`
`phenylpropy]amino]-cyclopentylcarbonyl}-(S)-isoserine, 1,1'-[dithiobis-[2(SJ-(2-
`
`methylbenzyl)—1~oxo—3,1-propanediyl]]—bis-(S)-isoserine, 1,1'-[dithiobis-[2(S)-(2—
`
`methylbenzyl)—‘1—oxo—3,‘l-propanediyl]]-bi‘s-(S)-methionine, N-(3-phenyl-2—(mercaptomethyl)-
`
`propionyl)-(S)-4-(methylmercapto)methionine, N-[Z-acetylthiomethyl-3-phenyl-propionyl]—3—
`
`aminobenzoic acid, N—[2—mercaptomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,
`
`N~[1-(2-Carboxy—4—pheny|butyl)—cyclopentanecarbonyl]-(S)—isoserine,
`
`N—[1—(acetylthiomethyl)cyclopentane—carbony|]—(S)—methionine ethyl ester.
`
`3(S)-{2-(acetylthiomethyl)—3—phenyl~propionyl]amimo~c—caprolactam; and the compounds
`
`disclosed in W0 93l’10773, particularly, N-(2-acetylthiomethyl—S—(2—methylphenyl)propionyl)—
`
`methionine ethyl ester.
`
`The compounds to be combined can be present as pharmaceutically acceptable
`
`salts.
`
`If these compounds have, for example, at least one basic center, they can form acid
`
`addition salts. Corresponding acid addition salts can also be formed having, if desired, an
`
`additionally present basic center. The compounds having at least one acid group. for
`
`example, COOH, can also form salts with bases. Corresponding internal salts may
`
`furthermore be formed, if a compound comprises, e.g., both a carboxy and an amino group.
`
`With respect to N—(3—carboxy-1—oxopropyl)-(4S)—p—phenylphenylmethyl)—4—amino—2R—
`
`methylbutanoic acid ethyl ester, preferred salts include the sodium salt disclosed in US.
`Patent No. 5,217,996, the triethanolamine salt and the tn's(hydroxymethyl)aminomethane
`
`salt. Preparation of the triethanolamine salt and the tris(hydroxymethyl)aminomcthane salt
`
`may be carried out as follows;
`
`Itiethanolamine
`
`To N-(B-carboxy-1-oxopropyl)—(4S)—p—phenylphenylmethyl)-4—amino-2R—methylbutanoic acid
`
`ethyl ester (349 mg, 0.848 mmol) is added 5 mL of ethyl ether and 0.113 mL (0.848 mmol)
`
`of triethanolamine in 1 mL of ethyl acetate. The solid was collected and dried melting at
`
`{SQ—71°C.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 013
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`Trisghydroxymethyll aminomethane
`
`To N—(B—carboxy—‘l-oxopropyl)-(4S)-p-phenylphenylmethyl)—4—amino—2R-methylbutanoic acid
`
`ethyl ester (3.2 g, 7.78 mmol) is added 32 mL of ethyl acetate and 940 mg (7.78 mmol)
`
`trr's(hydroxymethyl)aminomethane. The suspension is diluted with 45 mL of ethyl acetate
`
`and refluxed overnight (~20 hours). The reaction is cooled to 0°C, filtered, solid washed
`
`with ethyl acetate and dried melting at 114—115°C_
`
`It has surprisingly been found that, a combination of valsartan and a NEP inhibitor
`
`achieves greater therapeutic effect than the administration of valsartan, ACE inhibitors or
`
`NEP inhibitors alone and promotes iess angioedema than is seen with the administration of
`
`a vasopeptidase inhibitor alone. Greater efficacy can also be documented as a prolonged
`
`duration of action. The duration of action can be monitored as either the time to return to
`
`baseline prior to the next dose or as the area under the curve (AUC) and is expressed as
`
`the product of the change in blood pressure in millimeters of mercury (change in mmHg)
`
`and the duration of the effect (minutes, hours or days).
`
`Further benefits are that lower doses of the individual drugs to be combined
`
`according to the present invention can be used to reduce the dosage, for example, that the
`
`dosages need not only often be smaller but are also applied less frequently, or can be used
`
`to diminish the incidence of side effects. The combined administration of valsartan or a
`
`pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically
`
`acceptable salt thereof results in a significant response in a greater percentage of treated
`
`patients, that is, a greater responder rate results, regardless of the underlying etiology of the
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 014
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`
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`
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`condition. This is in accordance with the desires and requirements ofthe patients to be
`treated.
`
`It can be shown that combination therapy with valsartan and a NEP inhibitor results
`
`in a more effective anti-hypertensive therapy (whether for malignant. essential. reno—
`
`vascular. diabetic, isolated systolic or other secondary type of hypertension) through
`
`improved efficacy. as well as a greater responder rate. The combination is also useful in the
`
`treatment or prevention of heart failure. such as (acute and chronic) congestive heart failure.
`
`left ventricular dysfunction and hypertrophic cardiomyopathy. diabetic cardiac myopathy.
`
`supraventricular and ventricular arrhythmias. atrial fibrillation. atrial flutter or detrimental
`
`vascular remodeling It can further be shown that a valsartan and NEP inhibitor therapy
`
`proves to be beneficial in the treatment and prevention of myocardial infarction and its
`
`sequelae. A valsartan plus NEP inhibitor combination is also useful in treating
`
`atherosclerosis, angina (whether stable or unstable), and renal insufficiency (diabetic and
`
`non—diabetic). Furthermore. combination therapy using valsartan and a NEP inhibitor can
`
`improve endothelial dysfunction. thereby providing benefit in diseases in which normal
`
`endothelial function is disrupted. such as heart failure. angina pectoris and diabetes.
`
`Furthermore. the combination of the present invention may be used for the treatment or
`
`prevention of secondary aldosteronism. primary and secondary pulmonary hypertension.
`
`renal failure conditions. such as diabetic nephropathy, giomerulonephritis. scleroderma.
`
`glomerular sclerosis. proteinuria of primary renal disease and also renal vascular
`
`hypertension. diabetic retinopathy. the management of other vascular disorders. such as
`
`migraine. peripheral vascular disease. Raynaud's disease. luminal hyperplasia. cognitive
`
`dysfunction. such as Alzheimer's; glaucoma and stroke.
`
`The person skilled in the pertinent art is fully enabled to select a relevant test mode!
`
`to prove the efficacy of a combination of the present invention in the hereinbefore and
`
`hereinafter indicated therapeutic indications.
`
`Representative studies are carried out with a combination of valsartan and
`
`N—(3—carboxy-1-oxopropyl)-(4S)—p—pheny|phenylmethyl)—4-amino—2R—methylbutanoic acid
`
`ethyl ester. e_g_. applying the following methodology:
`
`Drug efficacy is assessed in various animal models including the
`
`deoxycorticosterone acetate-salt (DOCA-salt) rat and the spontaneously hypertensive rat
`
`(SHR). either maintained on a normal salt diet or with salt loading (4—8% salt in rat chow or
`
`1% NaCl as drinking water)
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 015
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 015
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`
`
`
`in
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`The DOCAmsalt test model utilizes either an acute or chronic study protocol. An
`
`acute study procedure involves assessment of the effects of various test substances over a
`
`six-hour experimental period using rats with indwelling femoral arterial and venous
`
`catheters. The acute study procedure evaluates test substances for their ability to reduce
`
`blood pressure during the established phase of DOCA—salt hypertension.
`
`In contrast, the
`
`chronic study procedure assesses the ability of test substances to prevent or delay the rise
`
`in blood pressure during the d_ey_e_lp_pme_nt__ph_a_se of DOCA-salt hypertension. Therefore,
`
`blood pressure will be monitored in the chronic study procedure by means of a
`
`radiotransmitter. The radiotransmitter is surgically implanted into the abdominal aorta of
`
`rats, prior to the initiation of DOCA-salt treatment and thus, prior to the induction of
`
`hypertension. Blood pressure is chronically monitored for periods of up to six weeks
`
`(approximately one week prior to DOCA-salt administration and for five weeks thereafter).
`
`Rats are anesthetized with 2-3% isofiurane in oxygen inhalant followed by Amytal
`
`sodium (amobarbital) 100 mgi‘kg, i.p. The level of anesthesia is assessed by a steady
`
`rhythmic breathing pattern.
`
`Acute study procedure:
`
`Rats undergo a unilateral nephrectomy at the time of DOCA implantation. Hair is clipped on
`
`the left flank and the back of the neck and scrubbed with sterile alcohol swabs and
`
`povidonefiodine. During surgery rats are placed on a heating pad to maintain body
`
`temperature at 37"C.
`
`A 20 mm incision is made through the skin and underlying muscle to expose the left kidney.
`
`The kidney is freed of surrounding tissue, exteriorized and two ligatures (3—0 silk) are tied
`
`securely around the renal artery and vein proximal to their juncture with the aorta. The renal
`
`artery and vein are then severed and the kidney removed. The muscle and skin wounds are
`
`closed with 4—0 silk suture and stainless steel wound clips, respectively. At the same time. a
`
`15 mm incision is made on the back of the neck and a three-week—release pellet (innovative
`
`Research of America, Sarasota‘ FL) containing DOCA (100 mgi'kg) is implanted
`
`subcutaneously (so). The wound is then closed with stainless—steel clips and both wounds
`
`are treated with povidoneliodine; the rats are given a post-surgical intramuscular (i.m.)
`
`injection of procaine penicillin G (100,000 U) and buprenorphine (005—01 mgi’kg) so. The
`
`rats are immediately placed on 1% NaCl + 0.2% KCI drinking water; this treatment continues
`
`for at least 3 weeks at which time the animals have become hypertensive and available for
`
`experimentation.
`
`-10-
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 016
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1015, p. 016
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`Forty-eight hours prior to experimentation, animals are anesthetized with isoflurane and
`
`catheters are implanted in the femoral artery and vein for measuring arterial pressure,
`
`collection of blood and administration of test compounds. Rats are allowed to recover for
`
`48 hours while tethered in a Plexiglas home cage, which also serves as the experimental
`
`chamber.
`
`Chronic study procedure:
`
`This procedure is the same as above except that rats are implanted with a radiotransmitter,
`
`7-10 days prior to the unilateral nephrectomy and initiation of DOCA and salt.
`
`In addition,
`
`rats do not undergo surgery for placement of femoral arterial and venous catheters.
`
`Radiotransmitters are implanted as described in Bazil et al., "Telemetric Monitoring of
`
`Cardiovascular Parameters in Conscious Spontaneously Hypertensive Rats", J.